Abstract
Alzheimer's disease (AD) represents a particular therapeutic challenge because its aetiology is very complex, with dynamic progression from preclinical to clinical stages. Several potential therapeutic targets and strategies were tested for AD, in over 2000 clinical trials, but no disease-modifying therapy exists. This failure indicates that AD, as a multifactorial disease, may require multi-targeted approaches and the delivery of therapeutic molecules to the right place and at the right disease stage. Opportunities to meet the challenges of AD therapy appear to come from recent progress in knowledge and methodological advances in the design, synthesis, and targeting of brain mRNA and microRNA with synthetic antisense oligonucleotides (ASOs). Several types of ASOs allow the utilisation of different mechanisms of posttranscriptional regulation and offer enhanced effects over alternative therapeutics. This article reviews ASO-based approaches and targets in preclinical and clinical trials for AD, and presents the future perspective on ASO therapies for AD.
Highlights
Alzheimer’s disease (AD) is an irreversibly progressing, ageingrelated neurodegenerative disorder affecting over 55 million people worldwide and the cause of 60-70% of dementia cases
Compared to traditional targeted molecular therapies, Antisense oligonucleotide (ASO) targeted to mRNA or miRNA seem to fulfil such requirements as they can be relatively delivered to the brain and they enable multi-targeting, adjusted sequentially to the disease stage
While so far ASOs have been tested for specific targeting of single mRNAs, their main advantage is the capacity for simultaneous regulation of several different transcripts
Summary
Alzheimer’s disease (AD) is an irreversibly progressing, ageingrelated neurodegenerative disorder affecting over 55 million people worldwide and the cause of 60-70% of dementia cases. AD is viewed as a progressing biological and clinical continuum It starts within the temporal area of the brain in the hippocampus and is marked by extracellular deposits of Ab peptides (senile plaques) and intraneuronal neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein. It is realised that the aetiology of sporadic, late-onset AD (SAD) is much more complex, with long-lasting, ageing-dependent dynamic development and progression from latent preclinical to clinical stages, modified by environmental risk factors [4,5]. It seems that ageing-related metabolic and systemic low-grade inflammation can trigger AD by blood-brain barrier (BBB) impairment and induction of neuroinflammation. The ASO mimics illustrate that RNA can play a vital effector function in molecular targeted therapies, whilst antagomiRs can target RNA
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